It has been shown that certain sapogenins and their derivatives (more particularly, sapogenins possessing a 5β hydrogen atom, and most particularly compounds possessing a 3-hydroxy group and a 5β-hydrogen atom, such as sarsasapogenin, episarsasapogenin, smilagenin and epismilagenin) have utility in the treatment of cognitive dysfunction and other conditions. Such activity is described, for example, in WO-99/48482, WO-99/48507, WO-01/49703, WO-02/079221 and WO-01/23406, the disclosures of which are incorporated herein by reference. The scheme for naming of the ring system and the carbon positions used herein is as given in these prior publications.
The literature describes methods for the synthesis of 3-hydroxy steroids and 3-hydroxy steroidal sapogenins. For example, the synthesis of 3β-hydroxy-5α-H steroids from the corresponding 3-keto-5α-H steroids has been effected with sodium borohydride in tetrahydrofuran and methanol or by using lithium aluminium hydride in diethyl ether (Helv. Chim. Acta, 66, 192-217 (1983)).
U.S. Pat. No. 3,875,195 (1975), the disclosure of which is incorporated herein by reference, describes the catalytic reduction of 3-keto-5β-H steroids to 3β-hydroxy-5β-H steroids in a lower carboxylic acid with Raney nickel and hydrogen under pressure. These workers note that the Meerwein-Ponndorf-Verley (MPV) reduction leads to mixtures of 3α-and 3β-hydroxy steroids in equal portions. The separation of such mixtures is reported to be difficult.
Since the introduction of the family of highly hindered trialkylborohydride reducing agents, commonly known as Selectrides®, beginning in the early 1970s (Brown et al., J. Am. Chem. Soc. 94, 7159-7161 (1972)), a number of publications have appeared in which these reducing agents have been applied to certain sterol synthetic methods. For example, in Steroids, 36, 299-303 (1980), Steroids, 45,39-51 (1985), J. Chem. Soc. Commun. 1239-1240 (1982), Tetrahedron, 40, 851-854 (1984), Helv. Chim. Acta, 66, 192-217 (1983), U.S. Pat. No. 6,150,336 (2000), and Tetrahedron, 45, 3717-3730 (1989), the disclosures of which are incorporated herein by reference, stereospecific selectride reductions of certain 3-keto-5β and 3-keto-5α steroids to their respective 3β-OH,5β-H and 3α-OH,5α-H sterols are described.
In relation to steroidal sapogenins, the art describes the synthesis of smilagenin by reduction of smilagenone with aluminium isopropoxide in isopropyl alcohol, the MPV reduction (Marker et al, J. Amer. Chem. Soc., 62, 2525 (1940)). Marker has reported the MPV reduction of sarsasapogenone to afford a mixture of sarsasapogenin and episarsasapogenin (Marker and Rohrmann, J. Amer. Chem. Soc., 61, 943 (1939)). The disclosures of these publications are incorporated herein by reference.
The art has also reported certain catalytic hydrogenations, as exemplified by Blunden's preparation of epitigogenin from tigogenone using hydrogenation over an Adams catalyst (platinum (IV) oxide) in glacial acetic acid containing 2% hydrochloric acid (J. Nat. Prod. 42, 478-482 (1979); Onderstepoort J. Vet. Res., 61, 351-359 (1994)). Marker has reported the hydrogenation of sarsasapogenone using Adams catalyst in ethanol to afford episarsasapogenin (Marker and Rohrmann, J. Amer. Chem. Soc., 61, 943 (1939)). The art has also reported sodium borohydride reduction, as exemplified by Miles's preparation of episarsasapogenin from sarsasapogenone using sodium borohydride (J. Agric. Food Chem., 41, 914-917 (1993)). The art has also reported lithium aluminium hydride reduction, as exemplified by Djerassi's preparation of epismilagenin from smilagenone (J. Am. Chem. Soc., 74, 422-424, (1952)) and Lajis's preparation of episarsasapogenin from sarsasapogenone (Steroids, 58, 387-389 (1993)). The disclosures of these publications are incorporated herein by reference.
U.S. Pat. No. 5,703,052 (1997), U.S. Pat. No. 5,807,834 (1998) and U.S. Pat. No. 5,939,398 (1999), the disclosures of which are incorporated herein by reference, report methods for the synthesis of 3α-hydroxy-5α-H sapogenins using K-Selectride® at low temperatures.
WO-02/079221 (published 10 Oct. 2002), describes in Example 6, a synthesis of episarsasapogenin by reduction of sarsasapogenone using lithium tri-tert-butoxyaluminohydride. However, this publication is not prior art in all countries.
The present invention seeks to provide an improved stereospecific synthesis of 3-hydroxy-5β-hydrogen steroidal sapogenins, and more preferably the 3β-hydroxy, 5β-H-sapogenins defined and described in the said publications WO-99/48482, WO-99/48507, WO-01/49703, WO-02/079221 and WO-01/23406, as well as their derivatives such as, for example, the corresponding saponins and other physiologically acceptable forms such as salts and esters, which may serve as pro-drugs.
In a most preferred embodiment, the present invention seeks to provide an efficient stereospecific synthesis of sarsasapogenin, smilagenin, episarsasapogenin, epismilagenin and their pro-drugs and other physiologically acceptable forms.